Process for the manufacture of 6-alkoxy-and 6-keto steroids and compounds obtained thereby



United States Patent "ice Meme, $1 3 2 and 3,032,565 CHa PROCESS FOR THE MANUFACTURE OF 6-ALK- OH OXY- AND 6-KETO STEROIDS AND COMPOUNDS R OBTAINED THEREBY 5 Raymond M. Dodson, Park Ridge, and Paul B. Sollman,

Wilmette, Ill., assignors to G. D. Searle & C0., Chicago, 11]., a corporation of Delaware No Drawing. Filed Aug. 24, 1960, Ser. No. 51,518 9 Claims. (Cl. 260-3914) The present invention relates to a novel process for the manufacture of 6-alkoxyand 6-keto-steroids, which 51, can be represented by the structural formulae 15 wherein R is hydrogen or a lower alkyl radical and R CH3 is a lower alkyl radical. These substances are useful as potent progestational agents, which lack the pronounced l side-effects characteristic of prior art compositions adapted for that purpose.

The lower alkyl radicals represented in the structural formulae supra are exemplified by methyl, ethyl, propyl, o: butyl, pentyl, heXyl, and the branched-chain isomers R' thereof. Lower alkanoyl radicals are, typically, formyl, 0R acetyl, propionyl, butyryl, valeryl, caproyl, and their and 5 branched-chain isomers, said groups being the acyl radicals of alkanoic acids containing fewer than 7 carbon 0 3 atoms. Examples of lower alkynyl radicals represented supra are ethynyl, propynyl, butynyl, pentynyl, hexynyl, I and their branched-chain isomers.

The instant process when applied to preparation of the compounds of structural formula O: 3 CH3 0133 H Q in which R is a lower alkyl radical, R is hydrogen or a methyl radical, Z is a methylene, hydroxymethylene, or carbonyl radical, and X is a carbonyl,

40 l r CH3 CH 0A (Learn 0R l OH-CHCH2CH2CH2CH O or O x wherein R, R, X and Z are as defined supra, involves B E 4 treatment of a compound of the structural formula radical, in which groups A is hydrogen or a lower 5 alkanoyl radical, B is hydrogen, a lower alkyl, or a lower CH? alkynyl radical, and D and E are members of the class comprising hydrogen, hydroXy, and (lower alkanoyl)oxy I radicals. l

Also within the scope of this invention are novel 6- alkoxy compounds of the structural formulae CH3 I 0 CH: IC=O with a lower alkanol such as methanol or ethanol together with a cupric halide, wherein the halide can be either chloride or bromide. In the preferred ernbodi.

9 ment of this process, 2 molecular equivalents of the cupric halide are used. As will be apparent from the disussi n. here u tter. u za on of ei ulp i halide leads to further reaction of the molecule. The reaction t per u may b between 0 nd 0 n the re! C action time may vary from 3Q minutes to 7 days, A1

though no catalyst is required, organic bases such as pyridine, trie'thylamine, etc., which can act as acid acceptors, may be included in the reaction mixture for the purpose of inhibiting the aforementioned further reaction of the 6-alkoxy product, and also to minimize possible degradation or rearrangement of sensitive sidechains.

It will be apparent to those skilled in the art that higher reaction temperatures will permit a decrease in the time necessary to complete the instant process. It has been determined also that higher temperatures and/or longer times are permissible when an acid acceptor is used. Examples of alternative optimum conditions are as follows:

(1) Heat at the reflux temperature for 1-2 hours in the presence of an acid acceptor.

(2) Allow to react at 2530 for l-3 days in the presence of an acid acceptor.

(3) Allow to react at 5 for 1-3 days with no acid acceptor included.

(4) Allow to react at 25-30 for 30 minutes-2 hours without an acid acceptor present.

6-alkoxy compounds represented supra can be converted to 3,6-diones, which are useful pharmacological agents. Specific examples involve heating a dioxane solution of 17/3-hydroxy-65-methoxyandrost-4-en-3-one, 613- methoxypregn-4-ene-3,ZO-dione, 6fl-methoxycholest-4-en- 3-one, or 21-hydroxy-GB-methoxypregn-4-ene-3,ZO-dione with dilute hydrochloric acid to produce 17,8-hydroxy-5aandrostane-3,6-dione, 5a-pregnane-3,6,20-trione, cholestane-3,6-dione, and 21-hydroxy-5a-pregnane-3,6,20-trione. The aforementioned 17B-hydroxy-5a-androstane-3,6-dione, for example, possesses anabolic and adrenocorticotropic activity while cholestane-3,6-dione is a cardiac stimulant.

The instant process, as disclosed supra, is useful for the production of a potent anti-inflammatory agents, exemplified by 17a,21-dihydroxy-6fi-methoxypregn-4-ene-3,ll, 20-trione, which was invented by Dr. Roy H. Bible.

When the instant process is carried out with greater than 2 molecular equivalents of the cupric halide in the absence of an acid acceptor, the product is a 6-dehydro- 6-alkoxy compound, as shown below:

on. on, CH8

wherein R, X, and Z are as defined supra.

Optimally, 4 molecular equivalents of the cupric halide are utilized to achieve the best yields of this product. The same time and temperature variables as discussed supra apply to the application of the instant process to the manufacture of these 6-dehydro-6-alkoxy compounds. A specific example of this application involves treatment of 17,8-hydroxyandrost-4 en-3-one with 4 molecular equivalents of cupric bromide in methanol solution to produce 17,8 hydroxy 6 methoxyandrosta-4,6-dicn-3-one. Likewise, l7a-acetoxypregn-4-ene-3,20-dione is converted to 1 7a-acetoxy-6-methoxypregna-4,6-diene-3,20-dione. The instant 6-dehydro-6-alkoxy compounds are useful as intermediates to the corresponding 6-keto compounds. This conversion involves reaction of the un- Saturated alkoxy compound with dilute hydrochloric acid in a suitable solvent such as dioxane. Typically, 17}?- acetoxy-6-methoxyandrosta-4,6-dien-3 -one is treated with dilute hydrochloric acid in dioxane to yield 17B-acetoxyandrost-4-ene-3,6-dione. These 6-keto compounds are pharmacologically active substances and are useful also as intermediates to the corresponding 6-methyl-6-dehydro compounds. For example, androst-4-ene-3,6,l7-trione, l7{3-hydrodyandrost-4-ene-3,6-dione, and pregn-4-ene-3,6, ZO-trione are estrogenic agents, while cholest-4-ene-3,6- dione is a cardiac stimulant. Conversion of these 6-keto compounds to the 6-methyl-6-dehydro substances involves first, protection of the 3-keto function by an ethylenedithio group, then reaction with methyl magnesium bromide followed by hydrolysis with mineral acid, and finally dehydration and cleavage of the 3-thioketal. l7a-acetoxypregn-4-ene-3,6,20-trione, for instance, is treated first with ethylenedithiol then with the aforementioned methyl Grignard reagent and hydrolyzed with hydrochloric acid to afford 17a-acetoxy-6-hydroxy-6-methylpregn-4-ene-3, 20-dione 3-ethylene thioketal. Reaction of the latter substance with aqueous hydrochloric acid and cadmium chloride in ethanol yields l7a-acetoxy-6-methylpregna-4,6- diene-3,20-dione, a known potent progrestational agent.

The invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given degrees centigrade C.). Quantities of materials are expressed in parts by weight unless otherwise noted.

EXAMPLE 1 Method A A mixture of 14.32 parts of androst-4-ene-3,17-dione, 22.34 parts of cupric bromide, 7.9 parts of pyridine, and 200 parts of methanol is heated at reflux for about 35 minutes, cooled, and poured into approximately 1500 parts of water. The resulting precipitate is collected by filtration, dried, and extracted with ethyl acetate. Concentration of the extract affords an oil, which is crystallized first from ether, then from acetone-hexane to yield 6B-methoxyandrost-4-ene-3,l7-dione, M.P. about 164- 166. It exhibits an unltraviolet maximum at about 233.5 millimicrons with a molecular extinction coetlcient of about 13,100.

Method B A mixture of 2.86 parts of androst-4-ene-3,17-di0ne, 4.47 parts of cupric bromide, and parts of methanol is stored at about 5 for about 7 days. Dilution of the reaction mixture with several volumes of water results in precipitation of the product, which is collected by filtration and recrystallized from aqueous methanol to afford 6B-methoxyandrost-4-ene-3,l7-dione, M.P. about l57-l59; [a] =+l22 (chloroform). It exhibits infrared maxima at about 5.73, 5.92, 6.18, 9.20, and 11.38 microns, and is identical with the compound obtained by Method A supra.

EXAMPLE 2 A mixture of 7.2 parts of pregn-4-ene-3,20-dione, 10.1 parts of cupric bromide, and 200 parts of ethanol is stirred at room temperature for about 30 minutes, then poured into about 900 parts of water. The resulting mixture is extracted with ether, and the organic layer is dried over sodium sulfate, then concentrated to an oil, which crystalizes on standing. A solution of this crystalline material in benzene is chromatographed on silica gel. Elution of the column with 10% ethyl acetate in benzene followed by crystallization from acetone-hexane affords pure 6,8-ethoxypregn-4-ene-3,20- dione, M.P. about 162163. This substance displays an ultraviolet maximum at about 235 millimicrons with an extinction coeflicient of about 13,900.

EXAMPLE 3 To a solution of 15.1 parts of 17 3-hydroxy-17ot-methylandrost-4-en-3-one in 60 parts of methanol containing 4.4 parts of pyridine is added 22.3 parts of cupric bromide, and the resulting slurry is stirred at room temperature for about 20 hours, then diluted with ethyl acetate. This mixture is washed successively with aqueous sodium bicarbonate and dilute ammonium hydroxide, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue is chromatographed on silica gel, and the column is eluted successively with benzene containing increasing concentrations of ethyl acetate. The 12-25% ethyl acetate in benzene eluates yield a fraction which is crystallized from ethyl acetate-hexane to produce 17,8-hydroxy-6fi-methoxy-17amethylandrost-4-en-3-one, M.P. about 149-150"; M +22 (chloroform); [a] =+15 (methanol). It exhibits maxima in the infrared at about 2.75, 5.92, 6.18, 9.15, and 11.38 microns, and an ultraviolet maximum at about 235 millimicrons with a molecular extinction coefficient of about 13,000.

EXAMPLE 4 A mixture of 5.4 parts of 1704,2ldihydroxypregn-4-ene- 3,11,20-trione, 2.7 parts of pyridine, 6.7 parts of cupric bromide, and 80 parts of methanol is stirred at room temperature for about 24 hours. Approximately 100 parts of saturated aqueous sodium bicarbonate and 100 parts of water are added, and the resulting mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, then concentrated to dryness, and this residue is chromatographed on silica gel. Elution of the column with 35% ethyl acetate in benzene followed by concentration of the eluate to dryness, and crystallization of the residue first from ethyl acetate, then from acetone results in pure 17a,21-dihydroxy-6fl-methoxypregn-4-ene-3,11,20-trione, M.P. about 233-238"; [a] =+l32 (chloroform). Infrared maxima are observed at about 2.85, 5.83, 6.00, 9.18, and 11.39 microns, and this substance displays also an ultraviolet absorption maximum at about 230.5 millimicrons with a molecular extinction coefficient of about 13,800.

EXAMPLE 5 To a solution of 3.85 parts of cholest-4-en-3-one in 240 parts of methanol is added, at 0, a solution of 4.47 parts of cupric bromide in 40 parts of methanol. The resulting mixture is stored at 0 for about 5 days, then filtered to remove the crystalline precipitate of 6fi-methoxycl1olest-4-en-3-one. This compound is characterized by infrared maxima at about 5.93. 6.19, 9.17, 9.29, and 11.39 microns, and by an ultraviolet maximum at about 236 millimicrons with a molecular extinction coefiicient of about 12,900.

EXAMPLE 6 To a solution of 3.72 parts of 21-acetoxypregn-4-ene- 3,20-dione in 160 parts of methanol is added, at 0, 4.47 parts of cupric bromide, and the resulting solution is kept at 0 for about 2 days. The crystalline precipitate which forms is collected by filtration and dried to yield 21-acetoxy-6,6-methoxypregn-4-ene-3,20-dione. It displays maxima in the infrared at about 5.70, 5.78, 5.93,

6.18, 8.02, 9.18 9.32, and 11.38 microns, and also an ultraviolet maximum at about 236.5 millimicrons with a molecular extinction coefficient of about 14,300.

EXAMPLE 7 tions of ethyl acetate. The 20% ethyl acetate in benzene. eluate afiords a fraction, which is crystallized successively from aqueous methanol, aqueous acetone, and acetone-hexane to yield 17a-acetoxy-6 8-methoxypregn-4- ene-3,20-dione, M.P. 254255; [a] =+2O (chloroform). It is further characterized by an ultraviolet absorption maximum at about 234.5 millimicrons with a molecular extinction coefficient of about 14,600.

The substitution of an equivalent quantity of cupric chloride for cupric bromide in the herein-described process also results in 17a-acetoxy-6/8methoxypregn-4-ene-3,20- dione.

XAM LE 8 To a solution of 3.14 parts of pregn-.4-ene-.3,20-di'one and 1.8 parts of pyridine in 40 parts of methanol is added a methanolic solution containing 4.47 parts of cupric bromide. The resulting green slurry is stirred at room temperature for about 24 hours, then treated With ether and water. The ether layer is separated, washed with Water, dried over anhydrous sodium sulfate, and concentrated to dryness. Successive crystallizations of the residue from ether-hexane, methylene chloride-hexane, and ethyl acetate-hexane results in pure 6,8-methoxypregn- 4-ene-3,20-dione, M.P. about 172-173; [a] =+127 (chloroform). Infrared maxima are observed at about 5.86, 5.93, 6.18, 9.18, and 11.37 microns, and an ultraviolet maximum at about 235 millimicrons with a molecular extinction coefiicient of about 13,700.

EXAMPLE 9 To a solution of 2.88 parts of 17;3-hydroxyandrost-4- en-3-one in parts of methanol is added, at 0-5, 4.47 parts of cupric bromide, and the resulting solution is stored at 0-5 for about 7 days, then poured into about 800 parts of water. The resulting crystalline precipitate is collected by filtration, dried, and recrystallized first from ether, then from methanol to yield pure 17,8-hydroxy- 6fl-methoxyandrost-4-en-3-one, M.P. about 213-217"; [a] =-|45 (chloroform). This substance exhibits infrared maxima at about 2.88, 6.01, 9.18, and 11.34 microns, and also an ultraviolet maximum at about 235 millimicrons with a molecular extinction coefiicient of about 13,000.

EXAMPLE 10 A solution of 7.73 parts of 17a-acetoxy-6a-methylpregn-4-ene-3,20-dione and 8.92 parts of cupric bromide in 800 partsof methanol is kept at 2 for about 3 days, then treated with approximately 75 parts of saturated aqueous sodium bicarbonate. The mixture is filtered, and the filtrate is concentrated to dryness to afford a residuewhich is extracted with ether. This extract is concentrated to a small volume, and the resulting crystals are collected by filtration and dried to yield crude 17a-acetoxy-6B-methoxy-6u-methylpregn-4-ene 3,20 dione, M.P. about 201-206". Recrystallization first from methanol, then from acetone-hexane results in the pure compound, M.P. 210-215; [a} =+7.5 (chloroform). It displays in- 210-215 [a] =-l7.5 (chloroform). It displays infrared maxima at about 3.52, 5.76, 5.97, 6.22, 7.89, 7.95, 9.27, 10.39, and 11.41 microns, and an ultraviolet maximum at about 235.5 millimicrons with an extinction coefiicient of about 13,500.

The substitution of equivalent quantities of oer-methyl- 17a-propionoxypregn-4-ene-3,20-dione and ethanol in the process of this example results in 6fi-ethoxy-6a-methyl- 17a-propionoxypregn-4-ene-3,20-dione.

EXAMPLE 11 To a solution of 1.8 parts of pyridine in 32 parts of methanol is added 3.26 parts of 17a-ethynyl-17B-hydroxy- 6a-methylandrost-4-en-3-one and 4.47 parts of cupric bromide, and the resulting slurry is stirred at room temperature for about 16 hours, then poured into saturated aqueous sodium bicarbonate. This aqueous mixture is extracted with ethyl acetate, and the extract is concentrated to an oil, which is then chromatographed on silica gel. The column is eluted first with ethyl acetate in benzene, then with 10% ethyl acetate in benezene. The latter eluate afiords a fraction which is crystallized first from aqueous methanol, then from acetone-hexane to yield 17a-ethynyl-1718-hydroxy-66-methoxy-6tat-methylandrost-4-en-3-one, M.P. about 216.52205 EXAMPLE 12 Method A Method B The procedure of Method A is conducted in the same manner as described therein, except that the reaction mixture is stored at 05 for about 3 days. In this instance the ethyl acetate extract of the precipitated crude product is concentrated to afford a solid residue, which is washed with ether, then recrystallized from ethyl acetate to produce 17/3 hydroxy 6-methoxyandrosta-4,6-dien-3-one, identical with the product of Method A.

EXAMPLE 13 The substitution of an equivalent quantity of 1706- acetoxypregn-4-ene-3,ZO-dione in either of the procedures, preferably procedure B, of Example 12 results in 17aacetoxy 6 methoxypregna-4,6-diene-3,20-dione, M.P. about 201-204". It displays ultraviolet maxima at about 247.5 and 303.5 millimicrons with molecular extinction coefiicients of about 8000 and 15,500, respectively.

EXAMPLE 14 A mixture of one part of 17B-hydroxy-6-methoxyandrosta-4,6-dien-3-one, 10 parts of pyridine, and 10 parts of acetic anhydride is allowed to stand at room temperature for about 4 hours, then poured slowly into 300 parts of cold water. The precipitate which forms is collected by filtration, dried, and recrystallized first from hexane then from acetone-hexane to afford 17B-acetoxy-6-methoxyandrosta-4,6-dien-3-one, M.P. about 161-162 (chloroform). This substance is further characterized by ultraviolet maxima at about 248.5 and 303 millimicrons with extinction coefficients of about 7,900 and 15,400,

respectively.

EXAMPLE 15 To a solution containing 30 parts of water and 12 parts of concentrated hydrochloric acid in 150 parts of dioxane is added 1.3 parts of 17 3-acetoxy-6-methoxyaudrosta-4,6-dien-3-one, and this reaction mixture is stored at room temperature for about 16 hours. Dilution with about 1000 parts of water results in precipit-a tion of the product, which is collected by filtration, dried, and recrystallized succesively from acetone-hexane and aqueous methanol to yield 17 8-acetoxyandrost-4-ene-3,6- dione, M.P. about 212-214. It displays a maximum in the ultraviolet at about 249.5 millimicrons with an extinction coefiicient of about 11,000.

By substituting an equivalent quantity of 17B-hydroxy- 6-methoxyandrosta-4,6-dien-3-one or 17a acetoxy-6- methoxypregna-4,6-diene-3,20-dione in the process of this example. 17B-hydroxyandrost-4-ene-3,6-dione and 17a-acetoxypregn-4-ene-3,6,20-trione are obtained.

EXAMPLE 16 The substitution of equivalent quantities of androst-4- ene-3,17-dione, pregn-4-ene-3,20-dione, 17,8-hydroxy-17otmethylandrost-4-en-3-one, cholest-4-en-3-one, or 21- acetoxypregn-4-ene-3,20-dione in Method B of Example 12 results in 6-methoxyandrosta-4,6-diene-3,17-dione, 6- methoxypregna 4,6 diene 3,20 dione, 17fi-hydroxy-6- methoxy-17a-methylandrosta-4,6-dien-3-one, 6-methoxycholesta-4,6-dien-3-one, and 2l-acetoxy-o-methoxypregna- 4,6-diene-3,20-dione, respectively.

EXAMPLE 17 The substitution of an equivalent quantity of ethanol for methanol in the process of Example 13 results in acetoxy-6-ethoxypregna-4,6-diene-3,20-dione.

EXAMPLE 18 To a solution of 36 parts of concentrated hydrochloric acid in 250 parts of dioxane containing 70 parts of water is added 1.53 parts of l7,6-hydroxy-6 8-methoxyandrost-4- en-3-one, and the mixture is heated at reflux for about 4 hours, then cooled and diluted with about 1500 parts of water. Concentration in vacuo to a small volume results in crystallization of 17fl-hydroxy-5a-androstane-3,6-dione, M.P. about 218221.

A solution of this 3,6-dione in 10 parts of acetic anhydride and 10 parts of pyridine is allowed to stand at room temperature for about 15 hours, then is diluted with water. The resulting precipitate is collected by filtration, and recrystallized from acetone-hexane to afiord 17fl-acetoxy-5ot-androstane-3,17-dione, which displays a double melting point at about 174179 and 188190.

By substituting equivalent quantities of 6,8-methoxypregn-4-ene-3,20-dione, 6,8-methoxycholest-4-en-3-one, or 21-hydroxy-6B-methoxypregn-4-ene-3,20 dione in the process of this example; 5u-pregnane-3,6,20-trione, M.P. about 235238, ([a] =+60), cholestane-3,6-dione, M.P. about 176-177, and 21-hydroxy-5a-pregnane- 3,6,20-trione, M.P. about 217-220, are obtained.

What is claimed is:

1. A process for the manufacture of compounds of the structural formula and radicals, in which groups A is a member of the class consisting of hydrogen and lower alkanoyl radicals, B is selected from the group consisting of hydrogen, lower alkyl, and lower alkynyl radicals, and D and E are selected from the group consisting of hydrogen, hydroxy, and lower alkanoyloxy radicals; which consists of treating a compound of the structural formula with a lower alkanol in the presence of not greater than 2 molecular equivalents of a cupric halide selected from the class consisting of cupric bromide and cupric chloride. 2. The process of claim I, conducted in the presence of an acid acceptor.

3. A compound of the structural formula CH; on. I: was

CE: OR

wherein R and R are lower alkyl radicals.

4. 17a-acetoxy 6p methoxy 6oz methylpregn-4-ene- 3,20-dione.

5. A compound of the structural formula OH "-020 R 7. In a process for the manufacture of compounds of the structural formula wherein X and Z are as defined in claim 1, the step which comprises treating a compound of the structural formula C H' CHI W with a lower alkanol in the presence of greater than 2 molecular equivalents of a cupric halide selected from the class consisting of cupric bromide and cupric chloride.

8. 17,8-hydroxy-6-methoxyandrosta-4,6-dien-3-one.

9. 17a-acetoxy-6-methoxypregna-4,6-diene-3,20-dione.

No references cited. 

1. A PROCESS FOR THE MANUFACTURE OF COMPOUNDS OF THE STRUCTURAL FORMULA 